Visual Acuity Outcomes in Diabetic Macular Edema With Fluocinolone Acetonide 0.2 µg/day Versus Ranibizumab Plus Deferred Laser (DRCR Protocol I)

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1 EXPERIMENTAL SCIENCE Visual Acuity Outcomes in Diabetic Macular Edema With Fluocinolone Acetonide 0.2 µg/day Versus Ranibizumab Plus Deferred Laser (DRCR Protocol I) Michael A. Singer, MD; Dan M. Miller, MD, PhD; Jeffrey G. Gross, MD; Craig M. Greven, MD; Barry Kapik, MS; Clare Bailey, MD, FRCOphth; Faruque Ghanchi, MBBS, FRCOphth; Baruch D. Kuppermann, MD, PhD INTRODUCTION BACKGROUND AND OBJECTIVE: Visual outcomes of the FAME study (0.2 µg/day fluocinolone acetonide [FAc]) and Protocol I (0.5 mg ranibizumab plus deferred laser) were compared using the area under the curve (AUC) analysis method. PATIENTS AND METHODS: Best-corrected visual acuity (BCVA) data collected during a period of 3 years of follow-up for patients enrolled in FAME or Protocol I were used to calculate AUC of the change in BCVA over a time curve. RESULTS: In the overall population, there was a greater treatment effect for ranibizumab plus deferred laser compared with FAc. However, for subgroups of pseudophakic eyes, eyes with chronic diabetic macular edema (DME), and pseudophakic eyes with chronic DME, ranibizumab plus deferred laser and FAc were not found to be significantly different. The ranibizumab group received a median of 14 injections during a 36-month period compared with a mean of 1.3 injections in the FAc group. CONCLUSION: In pseudophakic and chronic DME subgroups, FAc was comparable to ranibizumab plus deferred laser with fewer injections. [Ophthalmic Surg Lasers Imaging Retina. 2018;49: ] Diabetic macular edema (DME) is a severe, visionthreatening stage of diabetic retinopathy (DR) a leading cause of vision loss worldwide. 1 Although intravitreal anti-vascular endothelial growth factor (VEGF)-A injections have been demonstrated as effec- From University of Texas Health Science Center, San Antonio (MAS); Cincinnati Eye Institute, Cincinnati (DMM); Carolina Retina Center, Columbia, SC (JGG); Wake Forest Baptist Medical Center, Winston Salem, NC (CMG); Alimera Sciences, Alpharetta, GA (BK); University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom (CB); Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom (FG); and UC Irvine Health Gavin Herbert Eye Institute, Irvine, CA (BDK) Singer, Miller, Gross, etc.; licensee SLACK Incorporated. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International ( licenses/by/4.0). This license allows users to copy and distribute, to remix, transform, and build upon the article, for any purpose, even commercially, provided the author is attributed and is not represented as endorsing the use made of the work. Originally submitted January 17, Revision received June 21, Accepted for publication August 3, This study was presented at the American Academy of Ophthalmology Annual Meeting, New Orleans, November 11-14, Financial support for this study was provided by Alimera Sciences (Alpharetta, GA). The sponsor participated in data collection, data management, data analysis, interpretation of the data, preparation of the manuscript, and review of the manuscript. Employees of Alimera Sciences participated in conducting the study, data acquisition analysis, and reporting. Dr. Singer has received financial support from Aerpio, Allergan, Ampio, Genentech, and Regeneron. Dr. Miller has received financial support from Alcon, Genentech, and Regeneron; has been a consultant for Alimera and Bausch + Lomb; and has a personal financial interest in Vortex. Dr. Gross has received financial support from Acucela, Ohr, and Regeneron. Dr. Greven is involved in clinical trials with Genentech (Roche) and Allergan. Mr. Kapik is an employee of Alimera Sciences. Dr. Bailey is a consultant for Allergan, Alcon, Bayer, Alimera Sciences, Roche and Novartis. Dr. Ghanchi has been a consultant for Alimera, Allergan, Bayer, and Novartis and has received grants and funding from Allergan, Bayer, Novartis, psivida, Oraya, and Sakura. Dr. Kuppermann is involved in clinical research with Alcon, Alimera, Allegro, Allergan, Apellis, Genentech, GSK, J-Cyte, Neurotech, Ophthotech, Regeneron, and ThromboGenics, and has been a consultant for Aerpio, Alcon, Alimera, Allegro, Allergan, Ampio, Dose, Genentech, Glaukos, Novartis, Ophthotech, Regeneron, and SciFluor. The authors thank Shuo Yang, PhD, of Quorum Consulting for statistical support. Medical writing assistance was provided by Emma Mycroft at Helios Medical Communications, supported by Alimera Sciences. Address correspondence to Michael A. Singer, MD, 9157 Huebner Rd., San Antonio, TX 78240; msinger11@me.com. doi: / Ophthalmic Surgery, Lasers & Imaging Retina Healio.com/OSLIRetina

2 Figure 1. Integrated FAME trials study design, forming the FAME study. 14 BCVA = best-corrected visual acuity; DME = diabetic macular edema; FAc = fluocinolone acetonide tive in managing DME, reducing progression of DR, and treating neovascularization, 2,3 a broad spectrum of inflammatory events drives the pathogenesis and progression of DR 4 and the multifactorial nature of DR at all levels of severity has been established in human eyes. 5 The importance of continuous therapy to maintain the disease-modifying effects of pharmacotherapy on DR has been demonstrated in two separate reports, in which a reduction in injection frequency of anti-vegf therapy following a monthly injection regimen has resulted in worsening of DR. 6,7 The fluocinolone acetonide (FAc) 0.2 µg/day implant (Iluvien; Alimera Sciences, Alpharetta, GA) delivers the only continuous, multiyear therapy for DME as a daily micro-dose of FAc (0.2 µg/day) for 36 months. 8 Sustained, low-dose intravitreal steroid released by FAc 0.2 μg/day implants has been shown to reduce neuroinflammation in animal models. 9 In the FAME study, which compared efficacy in terms of change in best-corrected visual acuity (BCVA) for FAc 0.2 µg/day implant versus sham control in patients with DME, 8 the FAc implant demonstrated significant vision improvement in patients with DME for up to 36 months 8 and has also shown significant effects on slowing progression of proliferative DR and improving DR. 10 The area under the curve (AUC) method of efficacy analysis is an alternative measure of change in visual acuity (VA) that captures treatment benefit over an entire dosing/observation period, in contrast with typical measures of efficacy, which are based on a single time point measurement. For multiyear studies this is particularly relevant, especially considering the potential impact of shortterm data fluctuations when outcomes are assessed using individual time points. In addition, realworld treatment regimens often do not match those employed in pivotal clinical trials for short-acting therapies requiring regular intravitreal injections. September 2018 Vol. 49, No

3 Figure 2. DRCR.net Protocol I study design; data from sham and deferred laser treatment arms were incorporated into the current analysis. BCVA = best-corrected visual acuity; DME = diabetic macular edema AUC is being recognized as an important measure of therapy benefit for DR and has been previously used to assess the effect of anti-vegf therapy on proliferative DR. 3 The current analysis used the AUC method to compare the efficacy of FAc 0.2 µg/day with sham control to evaluate the FAc 0.2 µg/day implant in the treatment of DME. In addition, a comparative analysis was conducted with the publicly available Protocol I dataset, 11 where the AUC for the ranibizumab (Lucentis; Genentech, South San Francisco, CA) plus deferred laser arm was calculated. This arm was chosen because it had the best outcomes and is generally recognized as more closely reflecting the current standard of care. The AUC method is intended to allow more robust statistical comparison between trials than conventional measures of efficacy; additionally, these studies have similar inclusion and exclusion criteria. However, differences between the studies, such as the lack of a chronic subpopulation in Protocol I, introduce limitations to the current analysis. PATIENTS AND METHODS The FAME study, 12 consisting of two randomized, double-masked, sham injection-controlled, parallelgroup, multicenter trials (FAME A and B), was conducted during a 36-month period, as previously described. 13 Patients were randomized in a 2:1 ratio to FAc 0.2 µg/day or sham control injection. Treatment was administered to the study eye only (Figure 1). 14 At each visit, BCVA was assessed using either Early Treatment Diabetic Retinopathy Study (ETDRS) charts at 4 m or an electronic ETDRS (E-ETDRS) test at 3 m. The DRCR.net Protocol I trial 15 was a randomized, multicenter study conducted during a 36-month period (Figure 2). 2,16 Patients were randomly assigned to groups: sham injection plus prompt laser, ranibizumab 0.5 mg plus prompt laser, ranibizumab 0.5 mg plus deferred laser, or triamcinolone 4 mg plus prompt laser. Prompt laser was applied 3 to 10 days after the initial ranibizumab injection; deferred laser was applied at least 24 weeks following ranibizumab injection. In subjects with two eligible eyes, the right eye was randomly assigned to a treatment group; the left eye was assigned to sham plus prompt laser. AUC was calculated from the observed change in BCVA letter score from baseline through Month 36 using the trapezoidal rule. 3 For each subject, the summarized variable represented total AUC divided by the total number of days in the study. Individual patient AUC data were then used to calculate mean AUC for each subgroup. AUC analysis was performed for individual FAc 0.2 µg/day trials (FAME A and B) and the combined study 700 Ophthalmic Surgery, Lasers & Imaging Retina Healio.com/OSLIRetina

4 Figure 3. Summary of BCVA letter score and illustrative comparison of AUC analysis from (A) FAME A and (B) FAME B trials. AUC = area under the curve; BCVA = bestcorrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; FAc = fluocinolone acetonide population and compared with AUC for ranibizumab plus deferred laser in DRCR.net Protocol I. This arm was selected because it was considered to have an optimal BCVA outcome compared with the ranibizumab plus prompt laser and triamcinolone plus prompt laser arms. From baseline to Year 1, 75.5% of eyes in the ranibizumab plus deferred laser group, 69.0% of eyes in the ranibizumab plus prompt laser group, and 50.0% of eyes in the triamcinolone plus prompt laser group experienced a five-letter or greater improvement. From baseline to Year 5, 73.9% of eyes in the ranibizumab plus deferred laser arm experienced a five-letter or greater improvement compared with 66.1% of eyes in the ranibizumab plus prompt laser arm. 2,16 Further analyses were conducted on pseudophakic eyes (FAME and Protocol I), chronic DME eyes (DME duration 3 years, FAME only), and pseudophakic plus chronic DME eyes (FAME only). RESULTS Study Population In total, 953 patients were assessed in the FAME study with a mean age of 62.5 years; 188 participants were included in the ranibizumab plus deferred laser arm of Protocol I, with a mean age of 64 years. Baseline characteristics are further described in Table 1. 2,13 September 2018 Vol. 49, No

5 Figure 4. Summary of BCVA letter score and illustrative comparison of AUC from mean BCVA scores for FAc 0.2 µg/day and ranibizumab plus deferred laser: all cases, 3-year follow-up. AUC = area under the curve; BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; FAc = fluocinolone acetonide Number of FAc Treatments The number of FAc treatments administered during the FAME study was consistent across lens status and DME duration subgroups (Table 2). FAME AUC Outcomes A significant AUC-based treatment effect was observed for the FAc 0.2 µg/day implant versus sham control for FAME A and B independently (P =.03 and P <.001, respectively) (Figure 3). FAME Versus Protocol I Ranibizumab Plus Deferred Laser There was a significantly greater treatment effect for ranibizumab plus deferred laser compared with 0.2 µg/day FAc during the course of 36 months (8.43 letters/day compared with 5.18 letters/day, respectively; P =.002) (Figure 4). For pseudophakic and chronic DME subgroups, the AUC with FAc 0.2 µg/day compared with ranibizumab plus deferred laser was not found to be significantly different (P =.77 and P =.19, respectively) (Figure 5). For pseudophakic plus chronic DME eyes treated with FAc 0.2 µg/day and pseudophakic eyes treated with ranibizumab plus deferred laser, AUC was not significantly different (P =.90) (Figure 6). DISCUSSION The comparison of VA outcomes provided by the AUC method is more representative of the treatment effect over time than comparisons based on a single time point. This is especially true in larger studies, in which individual time points for comparison may vary considerably. AUC significantly favored FAc 0.2 µg/day during a period of 36 months compared with sham control in the FAME study. This outcome was replicated in the individual FAME A and B trials. In the overall FAME study population, the 36-month AUC was significantly greater for ranibizumab plus deferred laser than for FAc 0.2 µg/day (P =.002), partly because AUC was depressed in the FAc 0.2 µg/day group as a result of cataract development during the 12- to 18-month time period and consequent loss of VA (Figure 4). In a separate analysis of the FAME data, approximately 50% of patients (n = 188) treated with FAc 0.2 µg/day in the overall FAME study group underwent cataract extraction during the follow-up period. 17 Of the patients who underwent cataract extraction during the follow-up period, 52% (n = 97) had chronic DME. 17 Only 17% of patients in the sham group of the FAME study received cataract extraction during the follow-up period Ophthalmic Surgery, Lasers & Imaging Retina Healio.com/OSLIRetina

6 Figure 5. Summary of BCVA letter score and illustrative comparison of AUC from mean BCVA scores for FAc 0.2 µg/day and ranibizumab plus deferred laser: (A) Pseudophakic cases; (B) Chronic DME (DME duration 3 years) eyes and overall patient population. AUC = area under the curve; BCVA = best-corrected visual acuity; DME = diabetic macular edema; ETDRS = Early Treatment Diabetic Retinopathy Study; FAc = fluocinolone acetonide In this analysis of the FAME results and Protocol I, the visual outcomes achieved in pseudophakic cases treated with FAc 0.2 µg/day were not significantly different to those treated with ranibizumab plus deferred laser (P =.77). There was also no significant difference between the visual outcomes achieved in chronic DME treated with FAc 0.2 µg/ day and those of all Protocol I participants treated with ranibizumab plus deferred laser (P =.19). Cataract development and elevation of intraocular pressure (IOP) are known side-effects of intravitreal corticosteroid treatment; 8 the incidence of these ocular adverse events was greater in FAc treatment compared with ranibizumab treatment. Cataract was the most common adverse event in the FAME study, affecting 42.7% of all patients and 81.7% of phakic patients treated with the FAc 0.2 µg/day implant; IOP elevation considered an adverse event was observed in 37.1% of FAc 0.2 µg/day-treated patients compared with 11.9% of sham-control patients. 8 In the first year of Protocol I follow-up, only 6% of patients treated with ranibizumab plus deferred laser who were phakic at baseline required cataract extraction; seven eyes treated with ranibizumab plus deferred laser (4%) had either IOP elevation 10 mm Hg or greater, IOP increased to 30 mm Hg or greater, or initiation of IOP-lowering medication. 2 September 2018 Vol. 49, No

7 Figure 6. Summary of BCVA letter score and illustrative comparison of AUC from mean BCVA scores for FAc 0.2 µg/day (pseudophakic eyes with chronic diabetic macular edema) and ranibizumab plus deferred laser (pseudophakic cases). AUC = area under the curve; BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; FAc = fluocinolone acetonide The clinical benefit of FAc 0.2 µg/day appears to be comparable to that of ranibizumab plus deferred laser in pseudophakic and chronic DME eyes, as demonstrated by AUC analysis, with a lesser treatment burden. During the 36-month evaluation period, patients who received FAc 0.2 µg/day required a mean of 1.3 treatments irrespective of DME duration or baseline lens status. In contrast, the ranibizumab group required a median of 14 injections. Treatment with the FAc 0.2 µg/day implant therefore provides an alternative to anti-vegf therapy which, in selected patients, could provide similar benefit with a reduced treatment burden. A limitation of this analysis is its post-hoc nature and the fact that it involves clinical data from two different studies. Although conclusive statements cannot be made based on meta-type analyses, these comparisons are still valuable given that there are no head-to-head clinical trials comparing these two agents, which are both approved to treat DME in the US and chronic DME in Europe Even with these limitations, it should also be recognized that the ranibizumab plus deferred laser arm was specifically chosen because this is the ranibizumab arm in Protocol I with the optimal outcome. 3 Rather than combine the data for ranibizumab from the two arms, we felt that using only the arm with the best outcome offset some of the other limitations of this analysis. The ranibizumab plus deferred laser arm was also the most clinically relevant and reflective of the FAME study protocol in terms of additional therapies. Indeed, in the FAME study, rescue laser was only allowed 6 weeks after FAc was administered and subsequent treatments were allowed as frequently as every 12 months for persistent or recurrent edema. 8 In Protocol I, focal/ grid laser treatment was applied either promptly (3 to 10 days after the initial ranibizumab injection) or was deferred for at least 24 weeks. Additionally, with any comparisons between the FAME study and other phase 3 clinical trials for DME pharmacotherapies, it is important to recognize differences in the study population. For example, chronic and chronic-pseudophakic subgroups were not analyzed in Protocol I. Unlike most phase 3 studies, the population enrolled in FAME did not include any treatment-naive DME patients. This means that the FAME study population may have had more severe DME with potentially irreversible damage, which would only reduce the treatment effect seen 704 Ophthalmic Surgery, Lasers & Imaging Retina Healio.com/OSLIRetina

8 TABLE 1 Baseline Characteristics 2,13 FAME Protocol I Sham Control FAc 0.2 µg/day Ranibizumab Plus Deferred Laser Participants, n Age (Mean), Years Male, % Duration of Diabetes (Median, Interquartile Range), Years 16 (11 21) 16 (11 22) 17 (11 22) HbA1c (Median, Interquartile Range), % 7.4 ( ) 7.6 ( ) 7.5 ( ) Lens Status, % Phakic / % Pseudophakic 65 / / / 29* *28% posterior chamber intraocular lens, 1% anterior chamber intraocular lens FAc = fluocinolone acetonide; HbA1c = glycated hemoglobin TABLE 2 Fluocinolone Acetonide Treatments Administered During the FAME Study by Lens Status and Duration of DME Lens Status Pseudophakic 1.3 ± 0.5 Phakic 1.3 ± 0.6 DME Duration Chronic ( 3 years) 1.3 ± 0.6 Non-chronic (< 3 years) 1.3 ± 0.5 FAc = fluocinolone acetonide; SD = standard deviation; DME = diabetic macular edema Number of FAc Treatments (Mean ± SD) in the population. Although there were no approved pharmaceutical therapies for DME when the key phase 3 clinical study (FAME) was initiated, three pharmaceutical therapies have since been approved for the treatment of DME However, no comparison between FAc and these additional pharmaceutical therapies has yet been performed. The results of the Protocol I analysis of ranibizumab and laser treatment are now publicly available. 11 This meta-analysis comparison of the two studies was undertaken after the publication of the Protocol I analysis. The treatment burden, visual outcomes, and adverse events associated with each treatment were compared to allow clinicians to adjudicate the respective benefits of each treatment for their patients. Analyses of the impact of FAc treatment on DME are ongoing. However, there is an improvement in treatment burden with the FAc implant, which will have an impact on patient compliance and quality of life. An economic benefit may also be observed as a result of better DME management and fewer treatments. 25 REFERENCES 1. Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3): Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6): Writing Committee for the Diabetic Retinopathy Clinical Research Network, Gross JG, Glassman AR, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: A randomized clinical trial. JAMA. 2015;314(20): Tang J, Kern TS. Inflammation in diabetic retinopathy. Prog Retin September 2018 Vol. 49, No

9 Eye Res. 2011;30(5): Dong N, Xu B, Wang B, Chu L. Study of 27 aqueous humor cytokines in patients with type 2 diabetes with or without retinopathy. Mol Vis. 2013;19: Bressler SB, Liu DL, Glassman AR, et al. Change in diabetic retinopathy through 2 years: Secondary analysis of a randomized clinical trial comparing aflibercept, bevacizumab, and ranibizumab. JAMA Ophthalmol. 2017;135(6): Boyer DS, Nguyen QD, Brown DM, Basu K, Ehrlich JS, RIDE and RISE Research Group. Outcomes with as-needed ranibizumab after initial monthly therapy: Long-term outcomes of the phase III RIDE and RISE trials. Ophthalmology. 2015;122(12): Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10): Glybina IV, Kennedy A, Ashton P, Abrams GW, Iezzi R. Intravitreous delivery of the corticosteroid fluocinolone acetonide attenuates retinal degeneration in S334ter-4 rats. Invest Ophthalmol Vis Sci. 2010;51(8): Wykoff CC, Chakravarthy U, Campochiaro PA, Bailey C, Green K, Cunha-Vaz J. Long-term effects of intravitreal 0.19 mg fluocinolone acetonide implant on progression and regression of diabetic retinopathy. Ophthalmology. 2017;124(4): Laser-Ranibizumab-Triamcinolone for Diabetic Macular Edema (LRT for DME). Clinicaltrials.gov. show/nct Accessed October 3, Fluocinolone Acetonide Implant Compared to Sham Injection in Patients With Diabetic Macular Edema (FAME). Clinicaltrials. gov. Accessed October 3, Campochiaro PA, Brown DM, Pearson A, et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4): Singer M. Efficacy assessment of the 0.2 mg/day fluocinolone acetonide (FAc) intravitreal implants vs. sham control using the area under the curve (AUC) method. Poster presented at: American Society of Retina Specialists 34th Annual Meeting; August 9-14, 2016; San Francisco, CA. 15. Laser-Ranibizumab-Triamcinolone for Proliferative Diabetic Retinopathy (LRTforDME+PRP). Clinicaltrials.gov. Accessed October 3, Elman MJ, Ayala A, Bressler NM, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122(2): Yang Y, Bailey C, Holz FG, et al. Long-term outcomes of phakic patients with diabetic macular oedema treated with intravitreal fluocinolone acetonide (FAc) implants. Eye (Lond). 2015;29(9): Iluvien 190 micrograms intravitreal implant in applicator; summary of product characteristics EMc website. Accessed October 3, Iluvien (fluocinolone acetonide intravitreal implant) 0.19 mg for intravitreal injection; highlights of prescribing information. 2014a. label/2014/201923s000lbl.pdf. Accessed October 3, Lucentis intravitreal injection; prescribing information. 2014b. label/2014/125156s105lbl.pdf. Accessed October 3, Lucentis 10 mg/ml solution for injection; summary of product characteristics Accessed October 3, United States Food and Drug Administration Supplement Orig1s0069,s0076ltr.pdf. Accessed May 24, United States Food and Drug Administration Supplement Orig1s037ltr.pdf. Accessed May 24, United States Food and Drug Administration Supplement Orig1s009ltr.pdf. Accessed May 24, Quhill F, Beiderbeck A. Cost advantage of fluocinolone acetonide implant (Iluvien) versus ranibizumab in the treatment of chronic diabetic macular oedema. Glob Reg Health Technol Assess. 2017;4:e155-e Ophthalmic Surgery, Lasers & Imaging Retina Healio.com/OSLIRetina